Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold

ChemMedChem. 2018 May 8;13(9):931-943. doi: 10.1002/cmdc.201800053. Epub 2018 Apr 14.


With the discovery that serine hydroxymethyltransferase (SHMT) is a druggable target for antimalarials, the aim of this study was to design novel inhibitors of this key enzyme in the folate biosynthesis cycle. Herein, 19 novel spirocyclic ligands based on either 2-indolinone or dihydroindene scaffolds and featuring a pyrazolopyran core are reported. Strong target affinities for Plasmodium falciparum (Pf) SHMT (14-76 nm) and cellular potencies in the low nanomolar range (165-334 nm) were measured together with interesting selectivity against human cytosolic SHMT1 (hSHMT1). Four co-crystal structures with Plasmodium vivax (Pv) SHMT solved at 2.2-2.4 Å resolution revealed the key role of the vinylogous cyanamide for anchoring ligands within the active site. The spirocyclic motif in the molecules enforces the pyrazolopyran core to adopt a substantially more curved conformation than that of previous non-spirocyclic analogues. Finally, solvation of the spirocyclic lactam ring of the receptor-bound ligands is discussed.

Keywords: co-crystal structures; inhibitors; malaria; serine hydroxymethyltransferase; spiro compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Glycine Hydroxymethyltransferase / antagonists & inhibitors*
  • Glycine Hydroxymethyltransferase / metabolism
  • Humans
  • Indenes / chemical synthesis
  • Indenes / chemistry
  • Indenes / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Oxindoles / chemical synthesis
  • Oxindoles / chemistry
  • Oxindoles / pharmacology*
  • Parasitic Sensitivity Tests
  • Plasmodium / drug effects*
  • Plasmodium / enzymology
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Indenes
  • Ligands
  • Oxindoles
  • Spiro Compounds
  • 2-oxindole
  • Glycine Hydroxymethyltransferase
  • SHMT protein, human